A Passion for Science

By Mika Ono

What does it take to succeed in science? Persistence, curiosity, drive, and originality—at the very least. While many Scripps Research Institute investigators possess these qualities, the unusual career path of Elizabeth Wilson-Kubalek shows just how important these traits are.

Wilson-Kubalek left school at the age of 16 and never attended college. Yet she went on to build a reputation as an innovator in the field of electron microscopy, direct a lab at Scripps Research, and earn a Ph.D. from Scripps Research's top-ranked Kellogg School of Science and Technology. She has authored more than 30 papers, most recently one featured on the cover of the Journal of Structural Biology.

"Liz is passionate about science," says Sandra Schmid, chair of the Department of Cell Biology. "This strength enables her to be courageous as a scientist and driven in her quest to solve problems."

An Unusual Beginning

Wilson-Kubalek grew up in Edinburgh, Scotland, where her father worked in sales and her mother devoted most of her working years helping others—a volunteer for the Red Cross and a home-help aide for the sick and disabled. After graduating from Napier College, then a technical school, in 1974, she entered the workforce as a lab technician.

"I never thought of myself as going to college," says Wilson-Kubalek. "Nobody in my family had and it just didn't seem to be an option."

Her first job out of school was in a diagnostics lab, testing patient samples. She found the work routine. "I would keep notes looking for possible connections between various diseases, but that wasn't part of the job," she says. "I was trying to make the work interesting."

Not long afterward, she headed for Switzerland, where she hoped the career opportunities would be greater. Working at first in another diagnostic lab there, she began exploring her options. She visited a local biotech center, where she noticed an ad for a position in a crystallography lab.

The more she thought about working in research, the more the idea appealed to her. But she worried she was a long shot for the job because she had no background in crystallography. "I said, 'Please, just give me a chance,'" she recalls. "'Tell me which textbooks to read and I'll work for free for three months while I learn about the field.'"

Her enthusiasm landed her the job. Once she began work in the lab, which was led by Professor J.N. Jansonius, she found herself in her element. Noting her aptitude for research, many of her colleagues urged her to return to school. But attending college in Switzerland presented a particularly steep challenge—in addition to the regular rigors of the university system, lectures were in German and French, not English.

Instead of formal education, Wilson Kubalek channeled some of her energy and ambition into judo, where she rose to be a third-degree black belt and a member of the Swiss National Judo Team. "I would spend two to three hours a day training," she says. "I would use all my time off to travel to national and international competitions, for example in Spain or Austria."

In 1981, Wilson-Kubalek decided her career opportunities would be greater in the United States and she made the transition to the University of California, Berkeley, where she worked for a year with renowned crystallographer Sung-Hou Kim.

After a period where she returned to Switzerland briefly, navigated visa problems, and volunteered at the Columbia University Cancer Institute in New York, she found herself back in California looking for a job. Wilson-Kubalek decided on a direct approach.

"I had heard in the research community that Nigel Unwin was a leader in the field of electron microscopy," she says. "So one day I boldly walked into Stanford—not knowing anybody and with no job advertised—found Nigel, and told him, 'I think I'd be really great for this lab." He was taken aback and said he didn't have any money, but he ended up making space for me."

Not long afterward, Unwin found the funding to support Wilson-Kubalek, officially beginning Wilson-Kubalek's decade-long affiliation with Stanford University.

At Stanford, Wilson-Kubalek fell in love with electron microscopy, which has remained her consuming interest ever since. "Those early days were exciting," she says. "I love electron microscopy because you can actually look at the proteins. You don't have to wait for them to crystallize."

In the Unwin lab, Wilson-Kubalek began publishing scientific papers on the structure of the membrane receptor for acetylcholine, which enables the transmission of nerve impulses.

When Unwin left the university to return to Europe in 1987, Wilson-Kubalek joined two other Stanford labs, splitting her time between the groups of Jim Spudich, a well-known cell biologist, and Roger Kornberg, renowned for his work on the structural basis of transcription. This arrangement suited her well because she could capitalize on her expertise in electron microscopy, learn more cell biology techniques, and pursue two new areas of study. More publications followed, this time on the first structures of E. coli RNA polymerase, yeast RNA polymerase by electron crystallography, and the characterization of a mutant form of the molecular motor protein, myosin II.

In 1992, Wilson-Kubalek began working with Stanford's Pat Brown, renowned for being one of the founders of the now-widespread gene chip technology. The match was fortuitous. 

"In Pat's lab, I could work totally independently," she says. "He had unrestricted Howard Hughes money and he liked the fact that I was creative, so he wanted me to do whatever I wanted. I wasn't going to college, but I had scientific freedom."

Wilson-Kubalek used this freedom to examine the native structure of mature and immature murine leukemia virus by cryo-electron microscopy.

She also further developed a lipid layer crystallization technique that had been pioneered in the Kornberg lab, providing a general approach to two-dimensional crystallization of His-tagged proteins on lipid layers by introducing the concept of nickel-chelating lipids. (Since functional His-tags can be inserted in recombinant proteins, nickel-lipids can be used to concentrate and specifically orient such proteins and induce the formation of 2-D crystals.) Wilson-Kubalek demonstrated that this approach was feasible by forming two-dimensional crystals of the HIV-1 reverse transcriptase.

Scientists can now buy this nickel lipid from the company Avanti Polar Lipids, Inc.

Scripps Research Calls

In 1995, Scripps Research investigator Ron Milligan succeeded in his decade-long effort to recruit Wilson-Kubalek to work with him.

"Liz and I worked in the same group (Unwin's) at Stanford in the '80s," Milligan says. "I knew that she was a talented experimentalist and also extremely creative in her approach to science. Over the years, she has come up with a number of very original ideas."

In the Milligan lab, Wilson-Kubalek continued pursuing her interest in developing new techniques, adapting the two-dimensional lipid system to work in 3-D. This technique uses lipid nanotubes—which, as the name implies, are shaped like tiny tubes—as a scaffold to hold the crystallized proteins. This helical arrangement presents the proteins so that scientists can see many different views of the molecules.

"It's like looking at a statue in a museum," Wilson-Kubalek explains. "To see all views of it, all you have to do is walk around. If a protein is bound to a nanotube, and if it then forms a helical array you have all the views required to reconstruct the 3-D structure of the molecule"

Wilson-Kubalek notes that the method can be used to view proteins at a moderate resolution of between 10 and 20 angstroms. "That gives you the overall shape of your molecule," she says, "and that can be informative."

Eager to see her colleagues give the technique a try, she included a long methods section in one of her most recent papers (see Journal of Structural Biology, November 2005). "I think most scientists should have this technique at the end of their bench, because it is very simple to make these tubes," she says. "This is especially true here at Scripps Research, where we have access to such excellent electron microscopy facilities."

Wilson-Kubalek also began work investigating the structure of P97, a AAA ATPase protein that plays a role in membrane fusion and extraction of proteins from the endoplasmic reticulum for cytoplasmic degradation. Her studies also include the cytolysins, in particular perfringloysin O, a pore forming toxin that kills cells by forming larges holes in the cell membrane.

As her research progressed, her reputation in the field continued to grow. In 1998, Wilson-Kubalek was invited to give a talk at the Symposium on Electron Crystallography of Biological Macromolecules in Tahoe, California. She had given a number of high-profile talks before, but this time Deputy Director of the National Institutes of Health (NIH) Sue Schaffer was in the audience.

After the talk, Schaffer came up to Wilson-Kubalek to ask about her lab. Wilson-Kubalek explained that she didn't have a college background, so didn't run her own lab. But, to Wilson-Kubalek's surprise, Schaffer responded that there was nothing to stop her from writing her own grant. A college degree was not required—only a good idea and some institutional backing in the form of lab space and an appropriate title.

Wilson-Kubalek went back to Scripps Research and began asking about getting this institutional backing. She was amazed by the response.

"I didn't face any walls," says Wilson-Kubalek. "Bernie Gilula, who was chair of the Cell Biology department at the time, said, 'If Sue Schaffer said you can do this, we will make sure you can do this.' That was a big turning point for me."

Wilson-Kubalek applied for an NIH grant, received funding, and launched her research program on protein crystallization on lipid tubule substrates, hiring a research assistant and a postdoc in the process.

The Value of Flexibility

In the course of her research, Wilson-Kubalek kept in touch with her colleagues at Stanford. After being invited to give a talk at Stanford, she talked with Alice Gast, now at MIT, about the overlapping interests of their research. The research of a graduate student in the joint lab of Gast and Channing Robertson was leading him in the direction of Wilson-Kubalek's work. She offered to help out, saying that the student could spend some time in her lab working on his thesis project.

Without quite realizing what was happening, Wilson-Kubalek found herself as the student's dissertation co-advisor. She successfully shepherded the student through the process, helping him complete his project, pass his thesis defense, and matriculate from Stanford. The irony of the situation did not escape Wilson-Kubalek.

"At that point, I thought, 'This is ridiculous,'" she recalls. "'I can give someone a Ph.D. and not have one myself. I've got to do something about this.'"

She made tentative inquiries about earning her Ph.D. from Scripps Research's Kellogg School of Science and Technology. At Stanford, she had asked similar questions, but they had gone nowhere. "Scripps was different," she says. "[Dean] Jeff Kelly did a lot of ground work for me to see if I could be eligible for the Ph.D. program without a bachelor's degree."

Getting the green light from Kelly, Wilson-Kubalek applied to the Kellogg School program, listing her publications—more than two dozen at the time—and obtaining letters of recommendations from leading investigators. "I only asked people outside of Scripps to write letters for me," she says. "A lot of them thought I already had my Ph.D., so they were surprised when I asked."

In 2002, Wilson-Kubalek was accepted into the Kellogg School, where she was required to meet the same requirements for classes and dissertation work as any other student in the program.

She admits it was difficult to keep all the balls in the air—running her lab, learning to take exams for the first time ("It's one thing to share your knowledge as professional, and other thing to be tested on what you know."), applying for more grant money (this time for work on the structure and function of N-Ethylmaleimide Sensitive Factor), and parenting her then-six-year-old daughter. But somehow she did it.

From Wilson-Kubalek's point of view, the program's biggest benefits were the opportunities to explore fields outside her immediate area of expertise, learn about the latest technologies, and meet faculty from different departments across the institute. Of fields that were new to her, neurobiology and molecular medicine particularly excited her.

In 2005, she marched in the commencement procession, officially receiving her Ph.D. degree.

Schmid notes, "To me, Liz's story highlights the value of the flexibility of our graduate program. We focus on training good scientists rather than on producing paperwork."

For Wilson-Kubalek, who already had funding for her research, earning a Ph.D. was more of a personal achievement than a professional one. Her experience at the Kellogg School, however, has had professional repercussions.

"I met faculty members in many different fields," she says, "and that has opened new possibilities for collaboration."

Shortly after receiving her degree, Wilson-Kubalek began a collaboration with Associate Professor M.G. Finn, a chemist who participated in her thesis committee. The two researchers plan to bring her work on lipid substrates together with the techniques of "click chemistry," a modular protocol for organic synthesis developed by Scripps Research Professor K. Barry Sharpless. The results of the collaboration may have implications for biosensor applications and/or nanotechnology development.

Looking Ahead

With the Ph.D. under her belt, today Wilson-Kubalek is happy to be able to devote more of her attention to her research and her family.

Wilson-Kubalek looks forward to being part of what she considers to be the renaissance of her field. "Scripps is an exciting place to work in electron microscopy," she says. "Now that high-resolution x-ray crystallography structures of small proteins can be achieved quickly, the next step is to look at these proteins in a complex. Today's electron microscopy lets us study these proteins in a more functional, in vivo environment, a more native-like state. In the past, x-ray crystallographers and EM people were quite separate, but now—especially here at Scripps—there is more and more interaction."

Wilson-Kubalek's also plans to spend more time with her daughter, now ten, who hopes to be an inventor one day. Wilson-Kubalek is determined to provide her daughter with every opportunity to attend college early on in life.

As part of her mentoring of the next generation, Wilson-Kubalek hopes to find a way to have an impact on women scientists in general. As a first step, she has begun participating in the Network for Women Scientists (NWiS), which works on the Scripps Research's La Jolla campus to provide support, guidance, and opportunity for female scientists at the institute and to create awareness of issues that affect scientific career development and success.

Wilson will draw on her own experience to encourage others. "I was in a situation where I didn't see that I had any opportunity, because I hadn't gotten the education," she muses. "And yet, I did manage to get there. I would like to offer hope to people like myself. The bottom line for scientists is not what university you go to—it's that you're bold and determined, and that you work hard."

Send comments to: mikaono[at]scripps.edu

Liz Wilson-Kubalek was directing her own NIH-funded electron microscopy research before she decided to get her Ph.D.

This 3-D density map calculated from electron microscope images shows helical arrays of perfringolysin O on nickel-lipid nanotubes.